NO162257B - PROGRESS TEA FOR LIQUIDIZATION OF NATURAL GAS AND THEREOF. - Google Patents

PROGRESS TEA FOR LIQUIDIZATION OF NATURAL GAS AND THEREOF. Download PDF

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Publication number
NO162257B
NO162257B NO843794A NO843794A NO162257B NO 162257 B NO162257 B NO 162257B NO 843794 A NO843794 A NO 843794A NO 843794 A NO843794 A NO 843794A NO 162257 B NO162257 B NO 162257B
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formula
carbamic acid
ethyl
carbon atoms
benzenesulfonylureas
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NO843794A
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Norwegian (no)
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NO843794L (en
NO162257C (en
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Yu-Nan Liu
James Willers Pervier
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Air Prod & Chem
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Publication of NO162257B publication Critical patent/NO162257B/en
Publication of NO162257C publication Critical patent/NO162257C/en

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    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F25—REFRIGERATION OR COOLING; COMBINED HEATING AND REFRIGERATION SYSTEMS; HEAT PUMP SYSTEMS; MANUFACTURE OR STORAGE OF ICE; LIQUEFACTION SOLIDIFICATION OF GASES
    • F25J—LIQUEFACTION, SOLIDIFICATION OR SEPARATION OF GASES OR GASEOUS OR LIQUEFIED GASEOUS MIXTURES BY PRESSURE AND COLD TREATMENT OR BY BRINGING THEM INTO THE SUPERCRITICAL STATE
    • F25J1/00—Processes or apparatus for liquefying or solidifying gases or gaseous mixtures
    • F25J1/0002—Processes or apparatus for liquefying or solidifying gases or gaseous mixtures characterised by the fluid to be liquefied
    • F25J1/0022—Hydrocarbons, e.g. natural gas
    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F25—REFRIGERATION OR COOLING; COMBINED HEATING AND REFRIGERATION SYSTEMS; HEAT PUMP SYSTEMS; MANUFACTURE OR STORAGE OF ICE; LIQUEFACTION SOLIDIFICATION OF GASES
    • F25J—LIQUEFACTION, SOLIDIFICATION OR SEPARATION OF GASES OR GASEOUS OR LIQUEFIED GASEOUS MIXTURES BY PRESSURE AND COLD TREATMENT OR BY BRINGING THEM INTO THE SUPERCRITICAL STATE
    • F25J1/00—Processes or apparatus for liquefying or solidifying gases or gaseous mixtures
    • F25J1/003—Processes or apparatus for liquefying or solidifying gases or gaseous mixtures characterised by the kind of cold generation within the liquefaction unit for compensating heat leaks and liquid production
    • F25J1/0047—Processes or apparatus for liquefying or solidifying gases or gaseous mixtures characterised by the kind of cold generation within the liquefaction unit for compensating heat leaks and liquid production using an "external" refrigerant stream in a closed vapor compression cycle
    • F25J1/0052—Processes or apparatus for liquefying or solidifying gases or gaseous mixtures characterised by the kind of cold generation within the liquefaction unit for compensating heat leaks and liquid production using an "external" refrigerant stream in a closed vapor compression cycle by vaporising a liquid refrigerant stream
    • F25J1/0055—Processes or apparatus for liquefying or solidifying gases or gaseous mixtures characterised by the kind of cold generation within the liquefaction unit for compensating heat leaks and liquid production using an "external" refrigerant stream in a closed vapor compression cycle by vaporising a liquid refrigerant stream originating from an incorporated cascade
    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F25—REFRIGERATION OR COOLING; COMBINED HEATING AND REFRIGERATION SYSTEMS; HEAT PUMP SYSTEMS; MANUFACTURE OR STORAGE OF ICE; LIQUEFACTION SOLIDIFICATION OF GASES
    • F25J—LIQUEFACTION, SOLIDIFICATION OR SEPARATION OF GASES OR GASEOUS OR LIQUEFIED GASEOUS MIXTURES BY PRESSURE AND COLD TREATMENT OR BY BRINGING THEM INTO THE SUPERCRITICAL STATE
    • F25J1/00—Processes or apparatus for liquefying or solidifying gases or gaseous mixtures
    • F25J1/02—Processes or apparatus for liquefying or solidifying gases or gaseous mixtures requiring the use of refrigeration, e.g. of helium or hydrogen ; Details and kind of the refrigeration system used; Integration with other units or processes; Controlling aspects of the process
    • F25J1/0211—Processes or apparatus for liquefying or solidifying gases or gaseous mixtures requiring the use of refrigeration, e.g. of helium or hydrogen ; Details and kind of the refrigeration system used; Integration with other units or processes; Controlling aspects of the process using a multi-component refrigerant [MCR] fluid in a closed vapor compression cycle
    • F25J1/0212—Processes or apparatus for liquefying or solidifying gases or gaseous mixtures requiring the use of refrigeration, e.g. of helium or hydrogen ; Details and kind of the refrigeration system used; Integration with other units or processes; Controlling aspects of the process using a multi-component refrigerant [MCR] fluid in a closed vapor compression cycle as a single flow MCR cycle
    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F25—REFRIGERATION OR COOLING; COMBINED HEATING AND REFRIGERATION SYSTEMS; HEAT PUMP SYSTEMS; MANUFACTURE OR STORAGE OF ICE; LIQUEFACTION SOLIDIFICATION OF GASES
    • F25J—LIQUEFACTION, SOLIDIFICATION OR SEPARATION OF GASES OR GASEOUS OR LIQUEFIED GASEOUS MIXTURES BY PRESSURE AND COLD TREATMENT OR BY BRINGING THEM INTO THE SUPERCRITICAL STATE
    • F25J1/00—Processes or apparatus for liquefying or solidifying gases or gaseous mixtures
    • F25J1/02—Processes or apparatus for liquefying or solidifying gases or gaseous mixtures requiring the use of refrigeration, e.g. of helium or hydrogen ; Details and kind of the refrigeration system used; Integration with other units or processes; Controlling aspects of the process
    • F25J1/0243—Start-up or control of the process; Details of the apparatus used; Details of the refrigerant compression system used
    • F25J1/0257—Construction and layout of liquefaction equipments, e.g. valves, machines
    • F25J1/0262—Details of the cold heat exchange system
    • F25J1/0264—Arrangement of heat exchanger cores in parallel with different functions, e.g. different cooling streams
    • F25J1/0265—Arrangement of heat exchanger cores in parallel with different functions, e.g. different cooling streams comprising cores associated exclusively with the cooling of a refrigerant stream, e.g. for auto-refrigeration or economizer
    • F25J1/0267—Arrangement of heat exchanger cores in parallel with different functions, e.g. different cooling streams comprising cores associated exclusively with the cooling of a refrigerant stream, e.g. for auto-refrigeration or economizer using flash gas as heat sink
    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F25—REFRIGERATION OR COOLING; COMBINED HEATING AND REFRIGERATION SYSTEMS; HEAT PUMP SYSTEMS; MANUFACTURE OR STORAGE OF ICE; LIQUEFACTION SOLIDIFICATION OF GASES
    • F25J—LIQUEFACTION, SOLIDIFICATION OR SEPARATION OF GASES OR GASEOUS OR LIQUEFIED GASEOUS MIXTURES BY PRESSURE AND COLD TREATMENT OR BY BRINGING THEM INTO THE SUPERCRITICAL STATE
    • F25J1/00—Processes or apparatus for liquefying or solidifying gases or gaseous mixtures
    • F25J1/02—Processes or apparatus for liquefying or solidifying gases or gaseous mixtures requiring the use of refrigeration, e.g. of helium or hydrogen ; Details and kind of the refrigeration system used; Integration with other units or processes; Controlling aspects of the process
    • F25J1/0243—Start-up or control of the process; Details of the apparatus used; Details of the refrigerant compression system used
    • F25J1/0257—Construction and layout of liquefaction equipments, e.g. valves, machines
    • F25J1/0262—Details of the cold heat exchange system
    • F25J1/0264—Arrangement of heat exchanger cores in parallel with different functions, e.g. different cooling streams
    • F25J1/0265—Arrangement of heat exchanger cores in parallel with different functions, e.g. different cooling streams comprising cores associated exclusively with the cooling of a refrigerant stream, e.g. for auto-refrigeration or economizer
    • F25J1/0268—Arrangement of heat exchanger cores in parallel with different functions, e.g. different cooling streams comprising cores associated exclusively with the cooling of a refrigerant stream, e.g. for auto-refrigeration or economizer using a dedicated refrigeration means
    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F25—REFRIGERATION OR COOLING; COMBINED HEATING AND REFRIGERATION SYSTEMS; HEAT PUMP SYSTEMS; MANUFACTURE OR STORAGE OF ICE; LIQUEFACTION SOLIDIFICATION OF GASES
    • F25J—LIQUEFACTION, SOLIDIFICATION OR SEPARATION OF GASES OR GASEOUS OR LIQUEFIED GASEOUS MIXTURES BY PRESSURE AND COLD TREATMENT OR BY BRINGING THEM INTO THE SUPERCRITICAL STATE
    • F25J1/00—Processes or apparatus for liquefying or solidifying gases or gaseous mixtures
    • F25J1/02—Processes or apparatus for liquefying or solidifying gases or gaseous mixtures requiring the use of refrigeration, e.g. of helium or hydrogen ; Details and kind of the refrigeration system used; Integration with other units or processes; Controlling aspects of the process
    • F25J1/0243—Start-up or control of the process; Details of the apparatus used; Details of the refrigerant compression system used
    • F25J1/0279—Compression of refrigerant or internal recycle fluid, e.g. kind of compressor, accumulator, suction drum etc.
    • F25J1/0292—Refrigerant compression by cold or cryogenic suction of the refrigerant gas
    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F25—REFRIGERATION OR COOLING; COMBINED HEATING AND REFRIGERATION SYSTEMS; HEAT PUMP SYSTEMS; MANUFACTURE OR STORAGE OF ICE; LIQUEFACTION SOLIDIFICATION OF GASES
    • F25J—LIQUEFACTION, SOLIDIFICATION OR SEPARATION OF GASES OR GASEOUS OR LIQUEFIED GASEOUS MIXTURES BY PRESSURE AND COLD TREATMENT OR BY BRINGING THEM INTO THE SUPERCRITICAL STATE
    • F25J2220/00—Processes or apparatus involving steps for the removal of impurities
    • F25J2220/60—Separating impurities from natural gas, e.g. mercury, cyclic hydrocarbons
    • F25J2220/62—Separating low boiling components, e.g. He, H2, N2, Air
    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F25—REFRIGERATION OR COOLING; COMBINED HEATING AND REFRIGERATION SYSTEMS; HEAT PUMP SYSTEMS; MANUFACTURE OR STORAGE OF ICE; LIQUEFACTION SOLIDIFICATION OF GASES
    • F25J—LIQUEFACTION, SOLIDIFICATION OR SEPARATION OF GASES OR GASEOUS OR LIQUEFIED GASEOUS MIXTURES BY PRESSURE AND COLD TREATMENT OR BY BRINGING THEM INTO THE SUPERCRITICAL STATE
    • F25J2220/00—Processes or apparatus involving steps for the removal of impurities
    • F25J2220/60—Separating impurities from natural gas, e.g. mercury, cyclic hydrocarbons
    • F25J2220/64—Separating heavy hydrocarbons, e.g. NGL, LPG, C4+ hydrocarbons or heavy condensates in general
    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F25—REFRIGERATION OR COOLING; COMBINED HEATING AND REFRIGERATION SYSTEMS; HEAT PUMP SYSTEMS; MANUFACTURE OR STORAGE OF ICE; LIQUEFACTION SOLIDIFICATION OF GASES
    • F25J—LIQUEFACTION, SOLIDIFICATION OR SEPARATION OF GASES OR GASEOUS OR LIQUEFIED GASEOUS MIXTURES BY PRESSURE AND COLD TREATMENT OR BY BRINGING THEM INTO THE SUPERCRITICAL STATE
    • F25J2270/00—Refrigeration techniques used
    • F25J2270/12—External refrigeration with liquid vaporising loop
    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F25—REFRIGERATION OR COOLING; COMBINED HEATING AND REFRIGERATION SYSTEMS; HEAT PUMP SYSTEMS; MANUFACTURE OR STORAGE OF ICE; LIQUEFACTION SOLIDIFICATION OF GASES
    • F25J—LIQUEFACTION, SOLIDIFICATION OR SEPARATION OF GASES OR GASEOUS OR LIQUEFIED GASEOUS MIXTURES BY PRESSURE AND COLD TREATMENT OR BY BRINGING THEM INTO THE SUPERCRITICAL STATE
    • F25J2270/00—Refrigeration techniques used
    • F25J2270/18—External refrigeration with incorporated cascade loop

Description

Fremgangsmåte til fremstilling av oralt anvendbare benzolsulfonylurinstoffer med sterk og protrahert blodsukkersenkende virkning. Process for the production of orally usable benzenesulfonylureas with a strong and prolonged blood sugar-lowering effect.

Oppfinnelsen vedrører fremgangsmåte til fremstilling av oralt anvendbare benzolsulfonylurinstoffer med sterk og protrahert blodsukkersenkende virkning og med den generelle formel The invention relates to a process for the production of orally usable benzenesulfonylureas with a strong and prolonged blood sugar-lowering effect and with the general formula

hvori symbolene har følgende betydning: in which the symbols have the following meanings:

R a) alkyl, alkenyl med 2 til 8 karbonatomar, R a) alkyl, alkenyl with 2 to 8 carbon atoms,

b) lavere fenylalkyl, b) lower phenylalkyl,

c) lavere cykloheksylalkyl, c) lower cyclohexylalkyl,

d) endoalkylencykloheksyl, endoalkylencykloheksenyl, d) endoalkylenecyclohexyl, endoalkylenecyclohexenyl,

endoalkylencykloheksylmetyl eller endoalkylencyklor- endoalkylenecyclohexylmethyl or endoalkylenecyclohexyl-

heksenylmetyl med 1 til 2 endoalkylenkarbonatomer, hexenylmethyl with 1 to 2 endoalkylene carbon atoms,

e) lavere alkylcykloheksyl, lavere alkoksycykloheksyl, e) lower alkylcyclohexyl, lower alkoxycyclohexyl,

f) cykloalkyl med 5 til 8 karbonatomer, f) cycloalkyl with 5 to 8 carbon atoms,

g) cykloheksenyl, cykloheksenylmetyl, g) cyclohexenyl, cyclohexenylmethyl,

Z, Z' hydrogerijialogen, lavere alkyl eller lavere alkoksy,' Z, Z' the hydrogeryalogen, lower alkyl or lower alkoxy,'

X en mettet eller umettet hydrokarbonrest med 2 karbonatomer, X a saturated or unsaturated hydrocarbon residue with 2 carbon atoms,

Y en hydrokarbonrest med 1 til 3 karbonatomer, Y a hydrocarbon residue of 1 to 3 carbon atoms,

samt salter av de nevnte benzolsulfonylurinstoffer, og fremgangsmåten er karakterisert ved at enten as well as salts of the aforementioned benzenesulfonylureas, and the method is characterized by either

a) med gruppen a) with the group

i p-stilling substituerte benzolsulfonylisocyanafcer, -karbaminsyreestere, -tio karbaminsyreestere, -karbaminsyrehalogenider eller' -urinstoffer, omsettes med aminer som er substituert med gruppen R, eller p-substituted benzenesulfonyl isocyanafcers, -carbamic acid esters, -thiocarbamic acid esters, -carbamic acid halides or' -ureas, are reacted with amines which are substituted with the group R, or

b) sulfonamidér med formel b) sulfonamides of formula

eller deres salter omsettes med isocyanater, karbaminsyreestere, tiokarbaminsyreestere, karbaminsyrehalogenider eller urinstoffer som er substituert med, gruppen R, eller forbindelser med formel hvori A betyr en isourinstoffeter-, isotiourinstoffeter- eller paratan-syre-gruppe og R, X, Y, Z og Z' har den ovennevnte betydning, hydrolyseres eller d) i til benzolsulfonylurinstoffer med formel (I) svarende,benzolsulfonyl-tiourinstoffer utveksles svovelatomet med et oksygenatom på i og for seg kjent måte eller e) benzolsulfinyl- resp. -sulfenylurinstoffer svarende til benzolsulfonylurinstoffer med formel (I) oksyderes eller or their salts are reacted with isocyanates, carbamic acid esters, thiocarbamic acid esters, carbamic acid halides or ureas which are substituted with, the group R, or compounds of formula in which A means an isourea ether, isothiourea ether or paratanoic acid group and R, X, Y, Z and Z' has the above-mentioned meaning, is hydrolysed or d) in to benzenesulfonylureas with formula (I) corresponding to benzenesulfonyl-thioureas, the sulfur atom is exchanged for an oxygen atom in a manner known per se or e) benzenesulfinyl resp. -sulphenylureas corresponding to benzenesulphonylureas with formula (I) are oxidized or

f) i benzolsulfonylurinstoffer med formel f) in benzenesulfonylureas of formula

innføres ved acylering, eventuelt trinnvis på kjent måte, resten is introduced by acylation, possibly step by step in a known manner, the remainder

eller or

g) benzolsulfonylhalogenider med formel g) benzenesulfonyl halides of formula

hvori X, Y, Z og Z' har den ovenfor nevnte betydning, omsettes in which X, Y, Z and Z' have the above-mentioned meaning, are exchanged

med urinstoffer med formel with formula ureas

og reaksjonsproduktene eventuelt behandles med alkaliske midler for aaltdannelse. and the reaction products are optionally treated with alkaline agents for alt formation.

I det ovennevnte og de følgende definisjoner betyr "lavere alkyl" alltid en slik med 1 til 4 karbonatomer i rettlinjet eller forgrenet kjede. In the above and the following definitions, "lower alkyl" always means one with 1 to 4 carbon atoms in a straight or branched chain.

R kan eksempelvis bety: etyl, propyl, isopropyl, butyl, isobutyl, sek. butyl, rettlinjet eller forgrenet amyl (pentyl), heksyl, heptyl eller oktyl, de til de nevnte hydrokarbonrester tilsvarende rester med en etylenisk dobbeltbinding som allyl eller krotyl. Videre kan R bety: benzyl, a-fenyletyl, (3-f enyletyl, R can mean, for example: ethyl, propyl, isopropyl, butyl, isobutyl, sec. butyl, linear or branched amyl (pentyl), hexyl, heptyl or octyl, those to the aforementioned hydrocarbon residues corresponding residues with an ethylenic double bond such as allyl or crotyl. Furthermore, R can mean: benzyl, α-phenylethyl, (3-phenylethyl,

a-, p- eller f- fenylpropyl eller -fenylbutyler. a-, p- or f-phenylpropyl or -phenylbutyl.

Spesielt foretrukket er innen oppfinnelsens ramme slike forbindelser som som R inneholder i en cykloalifatisk eventuelt med alkyl resp. alkoksy substituert eller over alkylen til nitrogen-atomer bundet hydrokarbonrest. Som slike rester kan det eksempelvis nevnes: Cyklopentyl, cykloheksyl, eykloheptyl, cyklooktyl, metyl-cykloheksyl, etylcykloheksyl, propyl- og isopropylcykloheksyl, metoksycykloheksyl, etoksycykloheksyl, propoksy- og isopropoksy-cykloheksyl, idet alkyl- resp. alkoksygruppene fortrinnsvis kan fore-ligge i 4-stilling nemlig såvel i cis- som også i trans-stilling, cykloheksylmetyl, a-- eller g-cykloheksyletyl, endometylencykloheksyl (2,2,1-bicykloheptyl), endoetylencykloheksyl (2,2,2-bicyklooktyl), endometylencykloheksenylj endoetylencykloheksenyl, endometylen-cykloheksylmetyl, endoetylencykloheksylmetyl, endometylenjcyklo-heksenylmetyl eller endoetylencykloheksenylmetyl. Particularly preferred within the scope of the invention are such compounds which as R contains in a cycloaliphatic optionally with alkyl resp. Alkoxy substituted or above the alkylene to nitrogen atoms bonded hydrocarbon residue. Examples of such residues can be mentioned: Cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, methylcyclohexyl, ethylcyclohexyl, propyl- and isopropylcyclohexyl, methoxycyclohexyl, ethoxycyclohexyl, propoxy- and isopropoxy-cyclohexyl, whereby alkyl- or the alkoxy groups can preferably be present in the 4-position, namely in the cis- as well as in the trans-position, cyclohexylmethyl, α- or g-cyclohexylethyl, endomethylenecyclohexyl (2,2,1-bicycloheptyl), endoethylenecyclohexyl (2,2,2 -bicyclooctyl), endomethylenecyclohexenylj endoethylenecyclohexenyl, endomethylene-cyclohexylmethyl, endoethylenecyclohexylmethyl, endomethylenejcyclohexenylmethyl or endoethylenecyclohexenylmethyl.

X er en mettet eller umettet hydrokarbonrest med 2 X is a saturated or unsaturated hydrocarbon residue with 2

C-atomer som er substituert med 2 fenylrester som på sin side kan C atoms which are substituted with 2 phenyl residues which in turn can

ha substituenter som fluor, klor, brom, lavere alkyl eller lavere alkoksy. Penylrestene kan befinne seg på samme eller forskjellig karbonatomer av resten X. have substituents such as fluorine, chlorine, bromine, lower alkyl or lower alkoxy. The penyl residues can be on the same or different carbon atoms of the residue X.

Den med Y betegnede hydrokarbonrest er rettlinjet The hydrocarbon residue denoted by Y is rectilinear

eller forgrenét. or branched.

Alt etter naturen av leddene X og R vil i enkelte tilfelle den ene eller andre av de nevnte fremgangsmåter være uegnet for fremstilling av de under den generelle formel fallende individuelle forbindelser eller i det minste nødvendiggjøre forholdsregler til beskyttelse av aktive grupper. Slike forholdsvis sjeldent opptredende tilfeller kan lett erkjennes av fagfolk og det byr ikke på noen vanskeligheter i slike tilfelle med resultat å anvende en annen av de omtalte syntesemåter. Depending on the nature of the links X and R, in some cases one or the other of the aforementioned methods will be unsuitable for the preparation of the individual compounds falling under the general formula or at least require precautions to protect active groups. Such relatively rarely occurring cases can be easily recognized by professionals and it does not present any difficulties in such cases with results to use another of the synthesis methods mentioned.

De nevnte benzolsulfonyl-karbaminsyreestere resp. -tiokarbaminsyreestere kan i alkoholkomponenten ha en lavere alkyl-rest eller en fenylrest. The mentioned benzenesulfonyl-carbamic acid esters resp. -thiocarbamic acid esters can have a lower alkyl residue or a phenyl residue in the alcohol component.

Det samme gjelder for de R-substituerte karbaminsyreestere resp. de tilsvarende monotiokarbaminsyreestere. The same applies to the R-substituted carbamic acid esters or the corresponding monothiocarbamic acid esters.

Som karbaminsyrehalogenider egner det seg i første rekke kloridene. As carbamic acid halides, the chlorides are primarily suitable.

De som utgangsstoffer for fremgangsmåten ifølge oppfinnelsen angjeldende benzolsulfonylurinstoffer kan på den side av urinstoffmolekylet som er vendt bort fra sulfonylgruppen være usubstituert eller en eller to ganger substituert med fortrinnsvis lavere alkylrester eller arylrester, idet i tilfellet en substitusjon med to arylrester disse eventuelt kan være forbundet med hverandre ved en kjemisk binding eller over et broledd som -CH2-J -NH-, -0- eller -S-. Istedenfor på slik måte substituerte benzolsulfonylurinstoffer kan det også anvendes tilsvarende N-benzolsulfonyl-N'-acylurinstoffer, som ved N'-nitrogenatomet dess-uten kan være alkylert eller arylert og også bis-(benzolsulfonyl)-urinstoffer. Man kan eksempelvis behandle slike bis-(benzolsulfonyl)-urinstoffer eller N-benzolsulfbnyl-N'-acylurinstoffer med aminer R NH2. Videre er det mulig å gå ut fra urinstoffer med formel R-NH-C0-NH2 eller acylerte urinstoffer med formel R-NH-CO-NH-acyl, hvori acyl betyr en fortrinnsvis lavmolekylær alifatisk eller aromatisk syrerest eller nitrogruppen resp. fra fenylurinstoffer med formel R-NH-CO-NH-CgH,- eller fra difenylurinstoffer med formel R-NH-C0-N(CgH,-)2, idet fenylrestene kan være substituert og kan være forbundet med hverandre såvel direkte som også over et broledd som -CH2-, -NH-, -0- eller -S- eller fra N,N'-disubstituerte urinstoffer med formel R-NH-CO-NH-R og omsette disse med The benzenesulfonylureas used as starting materials for the method according to the invention may, on the side of the urea molecule facing away from the sulfonyl group, be unsubstituted or substituted once or twice with preferably lower alkyl residues or aryl residues, since in the case of a substitution with two aryl residues these may optionally be connected with each other by a chemical bond or across a bridge link such as -CH2-J -NH-, -O- or -S-. Instead of benzenesulfonylureas substituted in this way, corresponding N-benzenesulfonyl-N'-acylureas can also be used, which can also be alkylated or arylated at the N'-nitrogen atom and also bis-(benzenesulfonyl)ureas. One can, for example, treat such bis-(benzenesulfonyl)ureas or N-benzenesulfonyl-N'-acylureas with amines R NH2. Furthermore, it is possible to proceed from ureas with the formula R-NH-C0-NH2 or acylated ureas with the formula R-NH-CO-NH-acyl, in which acyl means a preferably low molecular weight aliphatic or aromatic acid residue or the nitro group resp. from phenylureas with the formula R-NH-CO-NH-CgH,- or from diphenylureas with the formula R-NH-C0-N(CgH,-)2, the phenyl residues can be substituted and can be connected to each other both directly and via a bridge link such as -CH2-, -NH-, -0- or -S- or from N,N'-disubstituted ureas of formula R-NH-CO-NH-R and reacting these with

substituerte benzolsulfonamider. substituted benzenesulfonamides.

Svovelatomets erstatning med et oksygenatom i de tilsvarende substituerte benzolsulfonyltiourinstoffer kan eksempelvis utføres ved hjelp av oksyder eller salter av tungmetaller, eller også ved anvendelse av oksydasjonsmidler som hydrogenperoksyd, natriumperoksyd eller salpetersyrling. Tiourinstoffene kan også avsvovles ved behandling med fosgen eller fosforpentaklorid. Som mellomtrinn dannede klormaursyreamidiner resp. -karbodiimider kan ved egnede forholdsregler som forsåpning eller vanntilleiring over-føres i benzolsulfonylurinstoffene. The replacement of the sulfur atom with an oxygen atom in the correspondingly substituted benzenesulfonylthioureas can be carried out, for example, by means of oxides or salts of heavy metals, or also by using oxidizing agents such as hydrogen peroxide, sodium peroxide or nitric acid. The thioureas can also be desulphurised by treatment with phosgene or phosphorus pentachloride. As an intermediate step, chloroformate amidines resp. -carbodiimides can be transferred into the benzenesulfonylureas by suitable precautions such as saponification or water addition.

Utførelsesformen av fremgangsmåten ifølge oppfinnelsen kan generelt variere sterkt med hensyn til reaksjonsbetingelsene og "tilpasses de eventuelle forhold. The embodiment of the method according to the invention can generally vary greatly with regard to the reaction conditions and can be adapted to the possible conditions.

Eksempelvis kan omsetningene gjennomføres under anvendelse av oppløsningsmidler ved værelsetemperatur eller ved forhøyet temperatur. For example, the reactions can be carried out using solvents at room temperature or at an elevated temperature.

Som utgangsstoffer anvender man på den ene side slike forbindelser som inneholder en med gruppen As starting materials, on the one hand, such compounds are used which contain a with group

substituert benzolrest. Som eksempler for bestanddelen av denne formel kommer det i betraktning: substituted benzene residue. As examples for the component of this formula, the following are considered:

De ved fremgangsmåten ifølge oppfinnelsen oppnåelige benzolsulfonylurinstoffderivater er verdifulle legemidler som utmerker seg med en sterk og fremfor alt langvarig blodsukkersenkende virkning. Deres blodsukkersenkende virkning kunne f.eks. fastslås på kaniner The benzenesulfonylurea derivatives obtainable by the method according to the invention are valuable drugs which are distinguished by a strong and, above all, long-lasting blood sugar-lowering effect. Their blood sugar-lowering effect could e.g. determined in rabbits

ved at man foret fremgangsmåteproduktene i doser på 10 mg/kg og bestemte blodsukkerverdien etter den bekjente metode av Hagedorn-Jensen over et lengere tidsrom. by feeding the process products in doses of 10 mg/kg and determining the blood sugar value according to the well-known method of Hagedorn-Jensen over a longer period of time.

Det ble eksempelvis fastslått at N-/~4-(B~<$,B-difenyl-propionamido>-etyl)-benzolsulfonyl7-N'-n-butyl-urinstoff etter 3 timer bevirker en blodsukkersenkning på 26% og N-/ 4-(3-<0,$-difenylpropionamido>-etyl)-benzolsulfonyl/-N'-(4-metyl-cykloheksyl)-urinstoff bevirker en blodsukkersenkning på 32 %. Sammenligner man hermed det som oralt antidiabetikum kjente N-(4-metyl-benzolsulfonyl)-N'-butyl-urinstoff, så fastslår man at ved den angitte dosering på 10 mg/kg på kaniner foregår det ikke mer noen blodsukkersenkning. lørst ved doser på 25 mg/kg og mer kan det iakttas en blodsukkerreaksjon. It was established, for example, that N-/~4-(B~<$,B-diphenyl-propionamido>-ethyl)-benzenesulfonyl7-N'-n-butyl-urea after 3 hours causes a blood sugar lowering of 26% and N-/ 4-(3-<0,$-diphenylpropionamido>-ethyl)-benzenesulfonyl/-N'-(4-methyl-cyclohexyl)-urea causes a 32% reduction in blood sugar. If one compares with this what is known as an oral anti-diabetic drug N-(4-methyl-benzenesulfonyl)-N'-butyl-urea, it is established that at the stated dosage of 10 mg/kg in rabbits no blood sugar lowering occurs. At least at doses of 25 mg/kg and more, a blood sugar reaction can be observed.

fremgangsmåteproduktenes sterke virkning blir spesielt tydelig når man nedsetter dosen. Administrerer man N/ 4-(g-<B,0-difenyl-propionamido>-etyl)-benzolsulfonyl7-N'-(4-metyl-cykloheksyl)-urinstoff i en dosering på 0,4 mg/kg på kaniner, så kan det stadig fastslås en tydelig blodsukkersenkning. the strong effect of the process products becomes particularly evident when the dose is reduced. If N/ 4-(g-<B,0-diphenyl-propionamido>-ethyl)-benzenesulfonyl7-N'-(4-methyl-cyclohexyl)-urea is administered in a dosage of 0.4 mg/kg to rabbits, then a clear drop in blood sugar can still be determined.

De beskrevne benzolsulfonylurinstoffer skal fortrinnsvis tjene til fremstilling av oralt administrerbare preparater med blodsukkersenkende virkning til behandling av diabetes mellitus og kan appliseres som sådanne eller i form av deres salter resp. i nærvær av stoffer som fører til en saltdannelse. Til saltdannelse kan det eksempelvis anvendes: alkaliske midler som alkali- eller jordalkalihydroksyder, -karbonater eller -bikarbonater, men også organiske baser, spesielt tertiære nitrogenbaser forutsatt at de er fysiologisk tålbare. The described benzenesulfonylureas should preferably serve for the production of orally administrable preparations with blood sugar-lowering effects for the treatment of diabetes mellitus and can be applied as such or in the form of their salts or in the presence of substances that lead to salt formation. For salt formation, for example, alkaline agents such as alkali or alkaline earth hydroxides, carbonates or bicarbonates can be used, but also organic bases, especially tertiary nitrogen bases, provided that they are physiologically tolerable.

Som medisinske preparater kommer det fortrinnsvis i betraktning tabletter som ved siden av fremgangsmåteproduktene inneholder de vanlige hjelpe- og bærestoffer som talkum, stivelse, melkesukker, tragant eller magnesiumstearat. As medicinal preparations, tablets are preferably taken into consideration which, in addition to the process products, contain the usual auxiliary and carrier substances such as talc, starch, milk sugar, tragacanth or magnesium stearate.

Et preparat som inneholder de beskrevne benzolsulfonyl-urinstof f er som virksomt stoff, f.eks. en tablett eller et pulver med eller uten de nevnte tilsetninger er hensiktsmessig bragt i en egnet dosert form. Som dosis velges da en slik som er tilpasset virkningen av det anvendte benzolsulfonylurinstoff og den Ønskede effekt. Hensiktsmessig utgjør doseringen pr. enhet ca. 0,5 til 100 mg, fortrinnsvis 2 til 10 mg, imidlertid kan det også anvendes betraktelig høyere eller lavere liggende doseringsenheter isom eventuelt før applikasjon må deles, resp. mangfoldiggjøres. Eksempel 1. N-/~4-(B-<B,B-difenyl-propionamido>-etyl)-benzolsulfonyl7-N'-n- butyl- urinstof f. ; A preparation containing the described benzolsulfonylureas as active ingredient, e.g. a tablet or a powder with or without the aforementioned additives is suitably brought into a suitable dosage form. The dose is then chosen which is adapted to the effect of the benzenesulfonylurea used and the desired effect. Appropriately, the dosage per unit approx. 0.5 to 100 mg, preferably 2 to 10 mg, however, considerably higher or lower lying dosage units can also be used if necessary before application must be divided, resp. be multiplied. Example 1. N-/~4-(B-<B,B-diphenyl-propionamido>-ethyl)-benzenesulfonyl7-N'-n-butyl-urea f. ;

201,4 g 4-( B-<B, B-difenyl-propionamido>-etyl)-benzol-sulfonamid (smp. 191-193°C), 13,8 g finpulverisert kaliumkarbonat og 250 ml aceton oppvarmes under omrøring og tilbakeløp i 1 time til acetonets kokning. Deretter tildrypper man under ytterligere kokning og omrøring 5 g (n) butylisocyanat og etteromrører 4 timer under ytterligere oppvarmning. Man inndamper i vakuum, oppløser det dannede residuum i vann, filtrerer og surgjør filtratet med saltsyre. Den dannede krystallgrøt suges fra og omkrystalliseres fra metanol. Smp. for N-/~~4-( |3-<g, B-difenyl-propionamido>-etyi)-benzolsulfonyl7-N'-n-butyl-urinstoff ligger ved l40-l42°C. 201.4 g of 4-(B-<B,B-diphenyl-propionamido>-ethyl)-benzenesulfonamide (m.p. 191-193°C), 13.8 g of finely powdered potassium carbonate and 250 ml of acetone are heated with stirring and reflux for 1 hour until the acetone boils. Then, during further boiling and stirring, 5 g (n) butyl isocyanate are added dropwise and stirred for 4 hours during further heating. One evaporates in a vacuum, dissolves the residue formed in water, filters and acidifies the filtrate with hydrochloric acid. The crystal slurry formed is sucked off and recrystallized from methanol. Temp. for N-[~4-(|3-<g,B-diphenyl-propionamido>-ethyl)-benzenesulfonyl7-N'-n-butyl-urea is at 140-142°C.

På analog måte får man av det innledningsvis nevnte sulfonamid og tilsvarende isocyanater: N-/-4-(B-< B,g-difenyl-propionamido>-etyl)-benzolsulfonyl7-N'-cykloheksyl-urinstoff med smp. 190-192°C (fra metanol), N-/~4-(B-< B,B-difenyl-propionamido>-etyl)-benzolsulfonyl7-N'-(4-metyl-cykloheksyl)-urinstoff (transform) med smp. l84-l86°C (fra metanol), In an analogous manner, the initially mentioned sulfonamide and corresponding isocyanates are obtained: N-/-4-(B-<B,g-diphenyl-propionamido>-ethyl)-benzenesulfonyl7-N'-cyclohexyl-urea with m.p. 190-192°C (from methanol), N-/~4-(B-<B,B-diphenyl-propionamido>-ethyl)-benzenesulfonyl7-N'-(4-methyl-cyclohexyl)-urea (transform) with m.p. l84-l86°C (from methanol),

av 4-( 3-<B, B-bis(4-klorfenyl)-propionamido>-etyl)-benzolsulfonamid med smp. l84-l85°C, N-/<->4-(B-<B,B-bis-(4-klorfenyl)-propionamido>-etyl)-benzolsulfonyl7-N'-cykloheksyl-urinstoff med smp. 168-170°C (fra metanol), N-/_—4- ( B-< B ,£-bis- (4-klorf enyl) -propionamido>-ety 1) -benzolsulf ony 17-N'-(4-metyl-cykloheksyl)-urinstoff (trans) med smp. 170-172°C of 4-(3-<B,B-bis(4-chlorophenyl)-propionamido>-ethyl)-benzenesulfonamide with m.p. 184-185°C, N-/<->4-(B-<B,B-bis-(4-chlorophenyl)-propionamido>-ethyl)-benzenesulfonyl7-N'-cyclohexyl-urea with m.p. 168-170°C (from methanol), N-/_—4- ( B-< B ,£-bis-(4-chlorophenyl)-propionamido>-ethyl 1)-benzenesulfony 17-N'-(4 -methyl-cyclohexyl)-urea (trans) with m.p. 170-172°C

(fra metanol), (from methanol),

av 4-( B-<3,B-bis-(4-klorfenyl)-akrylamido>-etyl)-benzolsulfonamid med smp. l8l-l83°C, of 4-(B-<3,B-bis-(4-chlorophenyl)-acrylamido>-ethyl)-benzenesulfonamide with m.p. l8l-l83°C,

N-/-4-(.B-<B, B-b is-(4-klorf enyl)-akrylamido>-etyl)-benzolsulf ony l7-N'-cykloheksyl-urinstoff med smp. 222-223°C (fra metanol/dimetylformamid), N-/-4-(.B-<B, B-b is-(4-chlorophenyl)-acrylamido>-ethyl)-benzenesulfonyl 17-N'-cyclohexyl-urea with m.p. 222-223°C (from methanol/dimethylformamide),

N- /~4-(B-< B,B-bis-(4-klorfenyl)-akrylamido>-etyl)-benzolsulfonyl7-N'-(4-metyl-cykloheksyl)-urinstoff (trans) med smp. 203-205°C N- /~4-(B-< B,B-bis-(4-chlorophenyl)-acrylamido>-ethyl)-benzenesulfonyl7-N'-(4-methyl-cyclohexyl)-urea (trans) with m.p. 203-205°C

(fra metanol/dimetylformamid), (from methanol/dimethylformamide),

av 4-( B-<oi, B-dif enylpropionamido>-etyl)-benzolsulf onamid (smp. l45°C), N-/—4-(B-<a,B-difenylpropionamido>-etyl)-benzolsulfonyl7-N'-cykloheksyl-urinstoff méd smp. 159-l6l°C (fra metanol), N-/~4-( B-<a, B-dif enylpropionamido>-etyl) -benzolsulf onyl7-N' - butylurinstoff med smp. 168-170°C (fra metanol) og of 4-(B-<oi,B-diphenylpropionamido>-ethyl)-benzenesulfonamide (m.p. l45°C), N-/—4-(B-<a,B-diphenylpropionamido>-ethyl)-benzenesulfonyl7- N'-cyclohexyl urea with m.p. 159-161°C (from methanol), N-/~4-(B-<a,B-diphenylpropionamido>-ethyl)-benzenesulfonyl7-N'-butylurea with m.p. 168-170°C (from methanol) and

N-/_ 4-(B-<a,B-difenylpropionamido>-etyl)-benzolsulfonyl7-N'-(4-metyl-cykloheksyl )-urinstof f (trans) med smp. 165-167°C (fra metanol), N-/_ 4-(B-<a,B-diphenylpropionamido>-ethyl)-benzenesulfonyl 7-N'-(4-methyl-cyclohexyl )-urea f (trans) with m.p. 165-167°C (from methanol),

av 4-( B-<ct, B-difenylakrylamido>-etyl)-benzolsulfonamid (smp. 180-182°C), of 4-(B-<ct,B-diphenylacrylamido>-ethyl)-benzenesulfonamide (m.p. 180-182°C),

N-/~4- ( B-<a, B-dif enylakrylamido>-etyl) -benzolsulfonyl7-N' - cykloheksyl-urinstoff med smp. l6l-l62°C (fra metanol) og N-/~4-(B-<a,B-difenylakrylamido>-etyl)-benzolsulfonyl7-N' -(4-metylcykloheksyl)-urinstoff (trans) med smp. 133-135°C (fra metanol), av 4-(B-<a-fenyl-B-4-klorfenylakrylamido>-etyl)-benzolsulfonamid (smp. 185-187°C), N-/~4-(B-<a,B-diphenylacrylamido>-ethyl)-benzenesulfonyl7-N'-cyclohexyl-urea with m.p. 161-162°C (from methanol) and N-/~4-(B-<α,B-diphenylacrylamido>-ethyl)-benzenesulfonyl 7-N' -(4-methylcyclohexyl)-urea (trans) with m.p. 133-135°C (from methanol), of 4-(B-<a-phenyl-B-4-chlorophenylacrylamido>-ethyl)-benzenesulfonamide (m.p. 185-187°C),

4-( 6-<a-f enyl-B-4-klorf enylakrylamido>-etyl) -benzolsulf onyl7-N'-cykloheksyl-urinstoff med smp. 196-197°C (fra metanol). 4-(6-<α-phenyl-B-4-chlorophenylacrylamido>-ethyl)-benzenesulfonyl7-N'-cyclohexylurea with m.p. 196-197°C (from methanol).

Eksempel 2. Example 2.

N- £~ 4-(B-< B,B-difenyl-propionamido>-ety1)-benzolsulfonyl7-N'-( 2, 5- endometylen- cykloheksylmetyl)- urinstoff. a) Man oppløser 1 g N-/~4-(B-<B,B-difenyl-propionamido>-etyl)-benzolsulfonyl7-N'-(2,5-endometylen-cykloheksylmetyl)-tio-urinstoff (fremstilt ved omsetning av 4-(B-<B,B-difenyl-propionamido>-etyl)-benzolsulfonamid og 2,5-endometylencykloheksylsennepsolj e, N-£~ 4-(B-<B,B-diphenyl-propionamido>-ethyl)-benzenesulfonyl7-N'-(2,5-endomethylene- cyclohexylmethyl)-urea. a) One dissolves 1 g of N-/~4-(B-<B,B-diphenyl-propionamido>-ethyl)-benzenesulfonyl7-N'-(2,5-endomethylene-cyclohexylmethyl)-thio-urea (prepared by reaction of 4-(B-<B,B-diphenyl-propionamido>-ethyl)-benzenesulfonamide and 2,5-endomethylenecyclohexyl mustard oil,

smp. 162-164°C, i 100 ml l-n natronlut og tilsetter 20 ml 30% hydrogenperoksyd. Man oppvarmer i 20 minutter på dampbad, filtrerer, klargjør filtratet med kull og får ved surgjøring av filtratet med saltsyre N-/<->4-(B-<B,B-difenyl-propionamido>-etyl)-benzolsulfony17-N'-(2,5-endometylen-cykloheksyl-metyl)-urinstoff. Stoffet smelter etter omkrystallisering fra metanol ved 191-192°C. m.p. 162-164°C, in 100 ml 1-1 caustic soda and add 20 ml 30% hydrogen peroxide. It is heated for 20 minutes on a steam bath, filtered, the filtrate clarified with charcoal and, by acidifying the filtrate with hydrochloric acid, N-/<->4-(B-<B,B-diphenyl-propionamido>-ethyl)-benzenesulfony17-N' -(2,5-endomethylene-cyclohexyl-methyl)-urea. The substance melts after recrystallization from methanol at 191-192°C.

b) 2,9 g N-/<->4-(B-<B,B-difenylpropionamido>-etyl)-benzolsulfonyl/-N'-(2,5-endometylen-cykloheksyl-metyl)-tiourinstoff b) 2.9 g N-/<->4-(B-<B,B-diphenylpropionamido>-ethyl)-benzenesulfonyl/-N'-(2,5-endomethylene-cyclohexyl-methyl)-thiourea

suspenderes i 100 ml metanol. Man tilsetter 0,1 g kaliumkarbonat og 1,1 g kvikksølvoksyd og omrører i 4 timer ved 40°C. suspended in 100 ml of methanol. 0.1 g of potassium carbonate and 1.1 g of mercuric oxide are added and stirred for 4 hours at 40°C.

Etter frafiltrering inndamper man. Det som seig harpiks dannede residuum av N-/~4-(B-<B,B-difenyl-propionamido>-etyl)-benzolsulfonyl7-N'-(2,3-endometylen-cykloheksylmetyl)-isourinstoff-metyleter oppvarmes med 250 ml konsentrert HC1 i 30 minutter på dampbad. Det dannede krystallinske bunnfall suges fra, vaskes med vann og omkrystaliiseres fra metanol. Man får i godt utbytte N/~4- (P-<P, p-dif enyl-propionamido>-etyl)benzolsulf onyl7-N' - (2,3-endometylencykloheksylmetyl)-urinstoff med smp. 191-192°C After filtration, it is evaporated. The residue of N-/~4-(B-<B,B-diphenyl-propionamido>-ethyl)-benzenesulfonyl-7-N'-(2,3-endomethylene-cyclohexylmethyl)-isourea methyl ether formed as a tough resin is heated with 250 ml of concentrated HC1 for 30 minutes on a steam bath. The formed crystalline precipitate is suctioned off, washed with water and recrystallized from methanol. One obtains in good yield N/~4-(P-<P, p-diphenyl-propionamido>-ethyl)benzenesulfonyl7-N' - (2,3-endomethylenecyclohexylmethyl)-urea with m.p. 191-192°C

Eksempel 3-N-/~4-(P-*P,p-difenyl-propionamido>-etyl)-benzolsulfonyl7-N'-(2,5-endometylen- A-^- cykloheksenyl- metyl) - urinstof f. ;14 g N-/_~4-( p-<p, p-difenylpropionamido>-etyl^-benzolsulf onyl7-karbaminsyre-metylest er (smp. 172-174°C) oppløses i 250 ml dioksan. Under omrøring tilsetter man 3>7 g 2,5-endometylen-cykloheksenyl-metylamin og koker i 5 timer under tilbakeløp. Derpå avdestilleres oppløsningsmidlet i vakuum, og residuet oppløses i l-n nafcronlut. Man filtrerer, surgjør filtratet med saltsyre og får N-/~4-( P-<P , P-dif enylpropionamido-etyl) -benzolsulf onyl7-N ' - ;(2,5-endometylen-ÅJ<->cykloheksenylmetyl)-urinstoff. Etter omkrystallisering fra metanol smelter stoffet ved 194-196°C• ;Eksempel 4- ;N-/<->4-(P- PjP-difenylpropionamid -etyl)-benzolsulfony17-N'-cykloheksylurinstoff. ' ;3,4 g N-/_~4-( p-aminoetyl) -benzolsulf onyl7-N'-cykloheksylurinstoff (smp. 203°C) oppvarmes med 2,5 g P,P-difenyl-! propionsyreklorid,og 1,5 g pyridin i 60 ml kloroform under omrøring i 12 timer ved 40°C. Man fjenraer oppløsningsmidlet på rotasjbns-fordamper, oppløser residuet i natriumkarbonatoppløsning, behandler med kull og surgjør. Utfellingen omkrystalliseres fra metanol. ;Smp. 190-192°C. ;Eks empel 5• ;N-/<->4-(p-<p,P-difenylpropionamid>-etyl)-benzolsulfonyl7-N'-cykloheksylurinstoff. ;A. 50 g natriumsulfit (Na2S0^ . 7H"20) oppløses i 150 ml ;vann dg blandes under omrøring med en suspensjon av 42,7 g 4-(P-<p,P-difenyl-propionamido>-etyl)-benzolsulfonsyreklorid og 150 ml kloroform. Ved tilsetning av noen dråper konsentrert natronlut holdes reaksjonsblandingen svakt alkalisk. Man omrører i 30 ;min. ved værelsesiemperatur og 1 time ved 80°G. Ved reaksjonen skal det organiske oppløsningsmiddel avdestillere langsomt. Residuet fortynnes med vann og oppløsningen surgjøres med fortynnet saltsyre. Det utfelte seige stoff gjenutfelles fra Na HCO^-oPPlØsning og fortynnet saltsyre. Man frasuger og tørker produktet i eksikator ;over P20^. Smp. 106-108°C. ;B. 11,8 g av det således dannede 4-(P-<P >P-difenyl-propion-amiio>-etyl) -benzolsulfinsyre innføres i 75 ml tionylklorid idet det inntrer heftig reaksjon. Man fjerner overskytende tionylklorid i vakuum ved 35°C og avryker det krystallinske residuum to ganger med benzol. Man innfører sulfinsyreklorid i en oppløsning av 4»3;g cykloheksylurinstoff og 40 ml pyridin og etteromrører i 20 min. ved værelsestemperatur. Deretter helles reaksjonsgodset på fortynnet saltsyre og det utfelte produkt suges fra. Det utrøres kort med fortynnet vandig ammoniakk og frasuges. ;Det i godt utbytte dannede N-/~4-(p-<p,p-difenyl-propionamido>-etyl)-benzolsulfinyl/-N'-cykloheksylurinstoff tørkes i eksikator over P20^°S smelter ved l63-l65°C. ;G. 2 g N-/_£-( p-<p, P-dif enyl-propionamido>-etyl) -benzolsulf inyl7-N'-cykloheksylurinstoff bringes i oppløsning i 60 ml dimetylformamid på dampbad og blandes med en varm vandig leiium-permanganatoppløsning .(inneholdene 1 g KMnO^) . Etter 2r3 min. frasuges brunstenen og filtratet blandes med vaanVog fortynnet saltsyre. ;Det således dannede N-//~4- ( P-P , P-dif enyl-propionamido-etyl)-benzolsulfonyl/-N<*->cykloheksylurinstoff suges fra. Gjenut-felt fra meget fortynnet vandig ammoniakk og fortynnet saltsyre og omkrystallisert fra metanol og smp. 190-192°C. Example 3-N-[4-(P-*P,p-diphenyl-propionamido>-ethyl)-benzenesulfonyl 7-N'-(2,5-endomethylene-A-^-cyclohexenyl-methyl)-urea f. ; 14 g N-/_~4-(p-<p,p-diphenylpropionamido>-ethyl^-benzenesulfonyl7-carbamic acid methyl ester) is (m.p. 172-174°C) dissolved in 250 ml dioxane. While stirring, 3 >7 g of 2,5-endomethylene-cyclohexenyl-methylamine and boil for 5 hours under reflux. The solvent is then distilled off in a vacuum, and the residue is dissolved in 1-n Nafcronic liquor. You filter, acidify the filtrate with hydrochloric acid and obtain N-/~4-( P -<P , P-diphenylpropionamido-ethyl)-benzenesulfonyl7-N ' - ;(2,5-endomethylene-ÅJ<->cyclohexenylmethyl)-urea. After recrystallization from methanol, the substance melts at 194-196°C• ;Example 4- ;N-/<->4-(P-PjP-diphenylpropionamide -ethyl)-benzenesulfonyl17-N'-cyclohexylurea. ' ;3.4 g N-/_~4-(p-aminoethyl)-benzenesulfonyl7- N'-cyclohexylurea (m.p. 203°C) is heated with 2.5 g of P,P-diphenyl-!propionic acid chloride and 1.5 g of pyridine in 60 ml of chloroform with stirring for 12 more at 40°C. The solvent is removed on a rotary evaporator, the residue is dissolved in sodium carbonate solution, treated with charcoal and acidified. The precipitate is recrystallized from methanol. ; 190-192°C. ;Example 5 • ;N-/<->4-(p-<p,P-diphenylpropionamide>-ethyl)-benzenesulfonyl7-N'-cyclohexylurea. A. 50 g of sodium sulphite (Na2S0^ . 7H"20) are dissolved in 150 ml; water and mixed with stirring with a suspension of 42.7 g of 4-(P-<p,P-diphenyl-propionamido>-ethyl)-benzenesulfonic acid chloride and 150 ml of chloroform. By adding a few drops of concentrated caustic soda, the reaction mixture is kept slightly alkaline. It is stirred for 30 minutes at room temperature and 1 hour at 80°G. During the reaction, the organic solvent must distill off slowly. The residue is diluted with water and the solution is acidified with diluted hydrochloric acid. The precipitated tough substance is reprecipitated from Na HCO^ solution and dilute hydrochloric acid. The product is suctioned off and dried in a desiccator; over P2O^. M.p. 106-108°C. ; B. 11.8 g of the thus formed 4- (P-<P >P-diphenyl-propion-amino>-ethyl)-benzenesulfinic acid is introduced into 75 ml of thionyl chloride as a vigorous reaction sets in. Excess thionyl chloride is removed in vacuo at 35° C. and the crystalline residue is precipitated twice with benzene. Sulfinic acid chloride is introduced into a solution of 4.3 g cyclohexanone xylurea and 40 ml of pyridine and after stirring for 20 min. at room temperature. The reaction mixture is then poured onto dilute hydrochloric acid and the precipitated product is sucked off. It is stirred briefly with diluted aqueous ammonia and suctioned off. The N-/~4-(p-<p,p-diphenyl-propionamido>-ethyl)-benzenesulfinyl/-N'-cyclohexylurea formed in good yield is dried in a desiccator over P20^°S melts at l63-l65°C . G. 2 g of N-/_£-(p-<p,P-diphenyl-propionamido>-ethyl)-benzenesulfinyl7-N'-cyclohexylurea are dissolved in 60 ml of dimethylformamide on a steam bath and mixed with a hot aqueous lithium permanganate solution .(contents 1 g KMnO^) . After 2 or 3 min. The brownstone is suctioned off and the filtrate is mixed with VaanVog diluted hydrochloric acid. The thus formed N-//~4-(P-P,P-diphenyl-propionamido-ethyl)-benzenesulfonyl/-N<*->cyclohexylurea is sucked off. Resuspended from very dilute aqueous ammonia and dilute hydrochloric acid and recrystallized from methanol and m.p. 190-192°C.

Eksempel 6. Example 6.

N-/~~4-(P-P<difenyl-propionamido>-etyl)-benzolsulfonyl/-N'-cykloheksylurinstoff. N-[~4-(P-P<diphenyl-propionamido>-ethyl)-benzenesulfonyl/-N'-cyclohexylurea.

7,1 g cykloheksylurinstoff oppløses i 250 ml absolutt benzol og under omrøring tilsettes 2,4 g av en ^ Ofo- ±g natrium-hydridoljesuspensjon. Man lar det etteromrøre i 2 l/2 time ved 7°°C av avkjøler deretter til værelsestemperatur. Nå tilsetter man langsomt under god omrøring en suspensjon av 10,7 g N-4-(p-difenyl-propionamido-etyl) -benzolsulf oklorid i I.50 ml abs. benzol. Man etteromrører i 4 timer ved. 70-80°C, avkjøler og blander med vann. Den vandige alkaliske oppløsning fraskiller man og uttrekker benzol-oppløsningeh to ganger med fortynnet vandig ammoniakk. De forenede alkaliske oppløsninger surgjøres og de utfelte krystaller frasuges. Etter gjenutfelling fra l-n vandig ammoniakk omkrystalliserer man fra metanol og får således N-//"4-( P-<dif enyl-propionamid>-etyl)-benzolsulfonyl7-N'-cykloheksylurinstoff av smp. 190-192°C. 7.1 g of cyclohexylurea are dissolved in 250 ml of absolute benzene and, with stirring, 2.4 g of a ^ Ofo-±g sodium hydryl oil suspension are added. It is left to stir for 2 l/2 hours at 7°C, then cooled to room temperature. A suspension of 10.7 g of N-4-(p-diphenyl-propionamido-ethyl)-benzenesulfochloride in 1.50 ml of abs. benzene. Stirring is continued for 4 hours. 70-80°C, cool and mix with water. The aqueous alkaline solution is separated and the benzene solution is extracted twice with dilute aqueous ammonia. The combined alkaline solutions are acidified and the precipitated crystals are suctioned off. After reprecipitation from 1-n aqueous ammonia, it is recrystallized from methanol and thus N-//"4-( P-<diphenyl-propionamide>-ethyl)-benzenesulfonyl7-N'-cyclohexylurea of mp 190-192°C is obtained.

Claims (1)

Fremgangsmåte til fremstilling av oralt anvendbare benzolsulfonylurinstoffer med sterk og protrahert blodsukkersenkende virkning og med den generelle formelProcess for the preparation of orally usable benzenesulfonylureas with a strong and prolonged blood sugar-lowering effect and with the general formula hvori symbolene har følgende betydning: R a) alkyl, alkenyl med 2-8 karbonatomer, b) lavere fenylalkyl, c) lavere cykloheksylalkyl, d) endoalkylencykloheksyl, endoalkylencykloheksenyl, endoalkylencykloheksylmetyl.eller endoalkylencyklo-heksenylmetyl med 1-2 endoalkylen-karbonatomer, e) lavere alkylcykloheksyl, lavere alkoksycykloheksyl, f) cykloalkyl med 5-8 karbonatomer eller g) cykloheksenyl, cykloheksenylmetyl, Z, Z' hydrogen, halogen, lavere alkyl eller lavere alkoksy,:in which the symbols have the following meaning: R a) alkyl, alkenyl with 2-8 carbon atoms, b) lower phenylalkyl, c) lower cyclohexylalkyl, d) endoalkylenecyclohexyl, endoalkylenecyclohexenyl, endoalkylenecyclohexylmethyl.or endoalkylenecyclohexenylmethyl with 1-2 endoalkylene carbon atoms, e) lower alkylcyclohexyl, lower alkoxycyclohexyl, f) cycloalkyl with 5-8 carbon atoms or g) cyclohexenyl, cyclohexenylmethyl, Z, Z' hydrogen, halogen, lower alkyl or lower alkoxy,: X en mettet eller umettet hydrokarbonrest med 2 karbonatomer,X a saturated or unsaturated hydrocarbon residue with 2 carbon atoms, Y en hydrokarbonrest med 1-3 karbonatomer,Y a hydrocarbon residue with 1-3 carbon atoms, og av deres salter, karakterisert ved at enten a) med gruppenand of their salts, characterized in that either a) with the group i p-stilling substituerte benzolsulfonylisocyanater, -karbaminsyreestere, -tio karbaminsyreestere, -karbaminsyrehalogenider eller -urinstoffer omsettes med aminer som er substituert med gruppen R eller deres salter, eller b) sulfonamider med formel j eller deres salter omsettes med isocyanater, karbaminsyreestere, tio. karbaminsyreestere, karbaminsyrehalogenider eller urinstoffer, som er substituert med gruppen R, eller c) forbindelser med formelp-position substituted benzenesulfonyl isocyanates, -carbamic acid esters, -thio carbamic acid esters, -carbamic acid halides or -ureas are reacted with amines which are substituted with the group R or their salts, or b) sulfonamides of formula j or their salts are reacted with isocyanates, carbamic acid esters, thio. carbamic acid esters, carbamic acid halides or ureas, which are substituted by the group R, or c) compounds of formula hvori A betyr en isourinstoffeter-, isotiourinstoffeter- eller parabansyregruppe og R, X, Y, Z og Z' har den ovennevnte betydning, hydrolyseres eller d) i til benzolsulfonylurinstoffer med formel (I) svarende benzolsulf onyl-tiourinstof f er utveksles svovelatomet med et oksygenatom på i og for seg kjent måte, eller e) benzolsulfinyl- resp. -sulfenylurinstoffer svarende til benzolsulf onylurinstof f er med formel (I) oksyderes eller f) i benzolsulfonylurinstoffer med formelin which A means an isourea ether, isothiourea ether or parabanic acid group and R, X, Y, Z and Z' have the above meaning, is hydrolyzed or d) in to benzenesulfonylureas of formula (I) corresponding to benzenesulfonylthioureas f is exchanged the sulfur atom with a oxygen atom in a manner known per se, or e) benzenesulfinyl- or -sulfenylureas corresponding to benzenesulfonylureas f with formula (I) are oxidized or f) in benzenesulfonylureas with formula innføres ved'acylering, eventuelt trinnvis på kjent måte, restenis introduced by acylation, optionally step by step in a known manner, the remainder eller g) benzolsulfonylhalogenider med formel hvori X, Y, Z og Z' har den ovenfor nevnte betydning, omsettes med urinstoffer med formel H2<N-CO-NHRor g) benzenesulfonyl halides of the formula in which X, Y, Z and Z' have the above-mentioned meaning, are reacted with ureas of the formula H2<N-CO-NHR og reaksjonsproduktene eventuelt behandles med alkaliske midler for saltdannelse.and the reaction products are optionally treated with alkaline agents for salt formation.
NO843794A 1983-10-25 1984-09-21 PROCEDURE FOR LIQUIDIZATION OF NATURAL GAS AND APPLIANCES THEREOF. NO162257C (en)

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